EP0970050B2 - Process for the preparation of 5,6-dihydro-11h-dibenzo a,d cyclohept-11-enes - Google Patents

Process for the preparation of 5,6-dihydro-11h-dibenzo a,d cyclohept-11-enes Download PDF

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Publication number
EP0970050B2
EP0970050B2 EP98907067A EP98907067A EP0970050B2 EP 0970050 B2 EP0970050 B2 EP 0970050B2 EP 98907067 A EP98907067 A EP 98907067A EP 98907067 A EP98907067 A EP 98907067A EP 0970050 B2 EP0970050 B2 EP 0970050B2
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low valent
valent titanium
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dihydro
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EP0970050A1 (en
EP0970050B1 (en
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William Paul Jackson
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Rolabo SL
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Rolabo SL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a process for the preparation of 5,6-dihydro-11H-dibenzo[a,d]cyclohept-5-enes such as loratadine.
  • the anti-histamine ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene) piperidine-1-carboxylate (loratadine) is a potent, long acting derivative of azatadine which shows negligible CNS side effects.
  • US-A-3,326,924 discloses processes for preparing various aza-dibenzo[a,d]-cycloheptene derivatives which involve production of a tricyclic ketone which is reacted with a Grignard reagent derived from 4-chloro-N-methyl piperidine. Dehydration gives the N-methyl product. The process is, however, hindered by the amount up to 30% of 1,6-addition product which is generated in the Grignard reaction causing problems in yield and purification.
  • US-A-4,282,233 discloses the preparation of loratadine from the product of the above reaction by demethylation/carboethoxylation.
  • Cid et al have reported (Tetrahedron, 1988, Vol 44, 6197-6200 ) that cross coupling reactions between a tricyclic ketone and a cyclic ketone can take place using low valent titanium to give biphenylmethylene piperidines or cyproheptadine.
  • the process suffers from the disadvantages that low valent titanium has to be generated using lithium metal which is hazardous on industrial scale and by the need to use about 12 equivalents of titanium reagent to prevent the reaction stopping at the diol stage.
  • the present invention provides a process for preparing 5,6-dihydro-11H-dibenzo[a,d]cyclohept-11-enes comprising reacting a compound of formula I: (wherein:
  • the compound of formula I is one in which R 2 denotes a halogen (eg. chloro) and R 1 , R 3 and R 4 denote hydrogen.
  • R 2 denotes a halogen (eg. chloro) and R 1 , R 3 and R 4 denote hydrogen.
  • the piperidone is one in which Y is the group CO 2 Et.
  • the reaction proceeds via an intermediate diol which, if desired, may be isolated by conducting the reaction at a lower temperature.
  • the olefin may be prepared from the intermediate diol in a subsequent step in a conventional manner.
  • the diol intermediate itself is novel and forms a further aspect of the invention.
  • the present invention provides a compound of formula III: (wherein R 1 , R 2 , R 3 , R 4 , X and Y are as defined hereinbefore).
  • the preferred compound is:
  • the compound of formula I and piperidone reagents are preferably reacted in substantially equimolar quantities; however an excess of either reagent can be tolerated, eg. the two reagents may be present in molar ratios of from 1:2 to 2:1, preferably 1.5:1 to 1:1.5, especially preferably 1.1:1 to 1:1.1.
  • Low valent titanium may be prepared in situ , using zinc eg. by reaction of a Ti(III) or Ti(IV) compound or complexes thereof with zinc.
  • a combination of titanium (IV) chloride or a complex thereof and zinc is used to generate low valent titanium. This embodiment has the advantage that zinc is relatively cheap and safe to use on an industrial scale.
  • Zn/Mg and Ti may be conveniently used in molar ratios of 4:1 to 1:1, preferably 3:1 to 2:1.
  • titanium reagent typically, a slight molar excess of titanium reagent is used over the amount of ketone present, although a larger excess may be used if desired.
  • the titanium reagent is preferably used at a molar ratio of from 0.5:1 to 6:1, preferably 1.5:1 to 4:1, particularly 2:1 to 3:1 relative to the compound of formula I.
  • the reaction may be conveniently conducted in etherial solvents such as for example tetrahydrofuran, dioxane and dimethoxyethane which are commonly used in coupling reactions involving titanium. Nevertheless ethyl acetate, iso-propyl acetate, t-butylacetate, DMF and acetonitrile are equally effective for this purpose. Tetrahydrofuran is preferred.
  • the reaction temperature may be conveniently in the range -10°C to the reflux temperature of the chosen solvent, but is preferably 100°C or less, especially 20 to 60°C.
  • the reaction temperature is preferably below 10°C.
  • Y may represent an N-protecting group and suitable groups includes acetyl, benzoyl, ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxy benzyl or 2,4-methoxybenzyl groups.
  • the optional subsequent cleavage of a N-protecting group may for example be carried out by conventional means eg. hydrolytically, hydrogenolytically or in the presence of an oxidising agent or acid.
  • Further examples of N-protecting groups and appropriate deprotection reactions are described in the literature (see for example McOmie, "Protecting groups in organic chemistry", Plenum, 1973 and Greene, “Protective groups in organic synthesis", Wiley Interscience 1981).
  • the process according to the invention is typically carried out at elevated temperature (eg. under reflux) for at least one hour, preferably 1-4 hours, particularly preferably 1-2 hours and at ambient pressure.
  • elevated temperature eg. under reflux
  • the process according to the invention provides a yield of a 5,6-dihydro-11H-dibenzo[a,d]cyclo-heptene typically in excess of 60%.
  • the mixture is filtered through celite and the celite washed with a further 50 ml toluene.
  • the organic phase is separated and dried over magnesium sulphate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Hydrogenated Pyridines (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Glass Compositions (AREA)
  • Iron Core Of Rotating Electric Machines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A process for preparing 10,11-dihydro-5H-dibenzo[a,d]cyclohept-5-enes (e.g. loratadine) by reacting a dibenzozuberone with an aliphatic ketone in the presence of low valent titanium.

Description

  • The present invention relates to a process for the preparation of 5,6-dihydro-11H-dibenzo[a,d]cyclohept-5-enes such as loratadine.
  • The anti-histamine ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene) piperidine-1-carboxylate (loratadine) is a potent, long acting derivative of azatadine which shows negligible CNS side effects.
    Figure imgb0001
    Figure imgb0002
  • The presence of the chlorine atom at the 8-position makes the chemistry of loratadine uniquely problematical and reductive preparations are ineffective because of the removal of chlorine at the 8-position.
  • US-A-3,326,924 (Villani et al) discloses processes for preparing various aza-dibenzo[a,d]-cycloheptene derivatives which involve production of a tricyclic ketone which is reacted with a Grignard reagent derived from 4-chloro-N-methyl piperidine. Dehydration gives the N-methyl product. The process is, however, hindered by the amount up to 30% of 1,6-addition product which is generated in the Grignard reaction causing problems in yield and purification. US-A-4,282,233 (Villani ) discloses the preparation of loratadine from the product of the above reaction by demethylation/carboethoxylation.
  • A synthetic route to loratadine is disclosed in US-A-4,659,716 (Villani et al ), US-A-4,731,447 (Schumacher et al ), US-A-4,873,335 (Schumacher et al ) and Journal of Organic Chemistry, 1989, Vol 54,2242-2244 (Schumacher et al.) which involves alkylation of the dianion of the t-butylamide of 2-cyano-3-methyl-pyridine, re-generation of the nitrile, Grignard reaction, cyclisation with HF/BF3 and demethylation/ carboethoxylation. This process is, however, hampered by the need to use hazardous organometallic reagents (LDA or butyl lithium) and a super-acid environment of liquid HF and BF3 gas.
  • Cid et al have reported (Tetrahedron, 1988, Vol 44, 6197-6200) that cross coupling reactions between a tricyclic ketone and a cyclic ketone can take place using low valent titanium to give biphenylmethylene piperidines or cyproheptadine. The process suffers from the disadvantages that low valent titanium has to be generated using lithium metal which is hazardous on industrial scale and by the need to use about 12 equivalents of titanium reagent to prevent the reaction stopping at the diol stage.
  • In general there exists a need for improved processes for preparing 5,6-dihydro-11H-dibenzo[a,d]-cycloheptenes which use less hazardous materials and provide improved yields and selectivity, particularly on industrial scale production. The present invention seeks to provide such an improved process.
  • It has now surprisingly been found that hetero-coupling of a tricyclic aromatic ketone with an aliphatic cyclic ketone in the presence of low valent titanium gives a high yield of unsaturated coupled product with only traces of homo-coupled ketones. Typically, the low valent titanium is present as titanium (II) and only a slight excess of titanium reagent is required.
  • Thus viewed from one aspect the present invention provides a process for preparing 5,6-dihydro-11H-dibenzo[a,d]cyclohept-11-enes comprising reacting a compound of formula I:
    Figure imgb0003
     (wherein:
    • X denotes nitrogen;
    • and R1, R2, R3 and R4 which may be the same or different independently denote hydrogen or a halogen (eg. F, Cl or Br))
    with a piperidone of formula
    Figure imgb0004
     (wherein:
    • Y denotes hydrogen, lower alkyl, CO2R5, SO2R5, CON(R5)2, SO2N(R5)2, CO2COR5 or a N-protecting group; and
    • R5 is hydrogen, a C1-12-alkyl group optionally substituted by one or more amino or C1-6-alkylamino groups, a phenyl group optionally substituted by one or more halo or C1-6-alkyl groups,a C7-12-phenylalkyl group optionally substituted at the phenyl by one or more halo or C1-6-alkyl groups, 2-piperidyl, 3-piperidyl or piperidyl substituted at the nitrogen atom by a C1-4-alkyl group) or a salt thereof in the presence of low valent titanium wherein said low valent titanium is generated from zinc/TiCl4. Preferably the low valent titanium consists essentially of Ti(II).
  • Preferably the compound of formula I is one in which R2 denotes a halogen (eg. chloro) and R1, R3 and R4 denote hydrogen.
  • Preferably the piperidone is one in which Y is the group CO2Et.
  • The reaction proceeds via an intermediate diol which, if desired, may be isolated by conducting the reaction at a lower temperature. The olefin may be prepared from the intermediate diol in a subsequent step in a conventional manner.
  • The diol intermediate itself is novel and forms a further aspect of the invention. Thus the present invention provides a compound of formula III:
    Figure imgb0005
     (wherein R1, R2, R3, R4, X and Y are as defined hereinbefore).
  • The preferred compound is:
    Figure imgb0006
  • The compound of formula I and piperidone reagents are preferably reacted in substantially equimolar quantities; however an excess of either reagent can be tolerated, eg. the two reagents may be present in molar ratios of from 1:2 to 2:1, preferably 1.5:1 to 1:1.5, especially preferably 1.1:1 to 1:1.1.
  • Low valent titanium may be prepared in situ, using zinc eg. by reaction of a Ti(III) or Ti(IV) compound or complexes thereof with zinc. In one preferred embodiment of the method according to the invention, a combination of titanium (IV) chloride or a complex thereof and zinc is used to generate low valent titanium. This embodiment has the advantage that zinc is relatively cheap and safe to use on an industrial scale.
  • In accordance with the invention, Zn/Mg and Ti may be conveniently used in molar ratios of 4:1 to 1:1, preferably 3:1 to 2:1.
  • Typically, a slight molar excess of titanium reagent is used over the amount of ketone present, although a larger excess may be used if desired.
  • The titanium reagent is preferably used at a molar ratio of from 0.5:1 to 6:1, preferably 1.5:1 to 4:1, particularly 2:1 to 3:1 relative to the compound of formula I.
  • The reaction may be conveniently conducted in etherial solvents such as for example tetrahydrofuran, dioxane and dimethoxyethane which are commonly used in coupling reactions involving titanium. Nevertheless ethyl acetate, iso-propyl acetate, t-butylacetate, DMF and acetonitrile are equally effective for this purpose. Tetrahydrofuran is preferred.
  • The reaction temperature may be conveniently in the range -10°C to the reflux temperature of the chosen solvent, but is preferably 100°C or less, especially 20 to 60°C. To prepare the diol the reaction temperature is preferably below 10°C.
  • As noted above, Y may represent an N-protecting group and suitable groups includes acetyl, benzoyl, ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxy benzyl or 2,4-methoxybenzyl groups. The optional subsequent cleavage of a N-protecting group may for example be carried out by conventional means eg. hydrolytically, hydrogenolytically or in the presence of an oxidising agent or acid. Further examples of N-protecting groups and appropriate deprotection reactions are described in the literature (see for example McOmie, "Protecting groups in organic chemistry", Plenum, 1973 and Greene, "Protective groups in organic synthesis", Wiley Interscience 1981).
  • The process according to the invention is typically carried out at elevated temperature (eg. under reflux) for at least one hour, preferably 1-4 hours, particularly preferably 1-2 hours and at ambient pressure.
  • The process according to the invention provides a yield of a 5,6-dihydro-11H-dibenzo[a,d]cyclo-heptene typically in excess of 60%.
  • The invention is illustrated in a non-limiting fashion by the following examples in which all ratios and percentages are by weight unless otherwise stated:
    • EXAMPLE 1 Preparation of Loratadine
  • 8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one (2.45g, 10 mmole) (see J. Heterocyclic Compounds, vol. 8, 1971, page 73) and 4-carboethoxypiperidone (1.8g, 10 mmole) are dissolved in 30 ml tetrahydrofuran. Zinc (5g, 78 mmole) is added and the mixture cooled to 0°C. Titanium tetrachloride (3 ml, 27 mmole) is added over about 10 minutes. The mixture is then heated at reflux for 1 hour. The mixture is added to 100 ml water and 50 ml toluene. Most of the aqueous phase is separated and the organic phase is washed with 20 ml ammonium hydroxide solution.
  • The mixture is filtered through celite and the celite washed with a further 50 ml toluene. The organic phase is separated and dried over magnesium sulphate.
  • The solvent is removed and the residue (3.75 g) is crystallised from butyl ether to give 2.5g loratadine (68%). HPLC shows the product to be >98% pure.

Claims (10)

  1. A process for preparing 5,6-dihydro-11H-dibenzo[a,d]cyclohept-11-enes comprising reacting a compound of formula I:
    Figure imgb0007
     (wherein:
    X denotes nitrogen;
    and R1, R2, R3 and R4 which may be the same or different independently denote hydrogen or a halogen)
    with a piperidone of formula (II)
    Figure imgb0008
    (wherein:
    Y denotes hydrogen, lower alkyl, CO2R5, SO2R5, CON(R5)2, SO2N(R5)2, CO2COR5 or a N-protecting group; and
    R5 is hydrogen, a C1-12-alkyl group optionally substituted by one or more amino or C1-6-alkylamino groups, a phenyl group optionally substituted by one or more halo or C1-6-alkyl groups, a C7-12-phenylalkyl group optionally substituted at the phenyl by one or more halo or C1-6-alkyl groups, 2-piperidyl, 3-piperidyl or piperidyl substituted at the nitrogen atom by a C1-4-alkyl group) or a salt thereof in the presence of low valent titanium wherein said low valent titanium is generated from zinc/TiCl4.
  2. A process as claimed in claim 1 wherein R2 is a halogen.
  3. A process as claimed in claim 1 or 2 wherein R1, R3 and R4 denote hydrogen.
  4. A process as claimed in any one of claims 1 to 3 wherein Y is CO2Et.
  5. A process as claimed in any preceding claim wherein Ti is present in a molar ratio range 1.5:1 to 4:1 relative to the compound of formula (I).
  6. A process as claimed in claim 5 wherein Ti is present in a molar ratio range 2:1 to 3:1 relative to the compound of formula (I).
  7. A process as claimed in any preceding claim comprising the preparation of an intermediate diol of formula III:
    Figure imgb0009
     (wherein R1, R2, R3, R4, Y and X are as defined in claim 1).
  8. A process as claimed in any preceding claim wherein said low valent titanium consists essentially of Ti(II).
  9. A process as claimed in any preceding claim wherein low valent titanium is prepared in situ.
  10. A process as claimed in any preceding claim for preparing Loratadine.
EP98907067A 1997-02-26 1998-02-26 Process for the preparation of 5,6-dihydro-11h-dibenzo a,d cyclohept-11-enes Expired - Lifetime EP0970050B2 (en)

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PCT/GB1998/000605 WO1998038166A1 (en) 1997-02-26 1998-02-26 Process for the preparation of 10,11-dihydro-5h-dibenzo[a,d]cyclohept-5-enes and derivatives thereof

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GB9703992D0 (en) * 1997-02-26 1997-04-16 Rolabo Sl Process
WO2013025882A2 (en) 2011-08-16 2013-02-21 Mt. Sinai School Of Medicine Tricyclic compounds as anticancer agents
CN112552230B (en) * 2020-12-11 2022-08-26 佛山普正医药科技有限公司 Synthetic method of cyproheptadine hydrochloride

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VILLANI, F.J. ET AL.: "Arzneim. Forsch./Drug Res. 36(II)", 1986, pages: 1311 - 1314 †
WEISSENSTEINER, W. ET AL.: "J. Org. Chem.", vol. 53, 1988, pages: 3988 - 3996 †

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ES2149737T1 (en) 2000-11-16
CA2282480A1 (en) 1998-09-03
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DE69802171T3 (en) 2010-07-08
DE69802171T2 (en) 2002-07-04
US6093827A (en) 2000-07-25
DK0970050T3 (en) 2002-02-11
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EP0970050A1 (en) 2000-01-12
GB9703992D0 (en) 1997-04-16
EP0970050B1 (en) 2001-10-24
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